Molecular mechanism of action and safety of 5-(3-chlorophenyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione - a novel anticonvulsant drug candidate

Abstract

Previously, it was found that 5-(3-chlorophenyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP-315) effectively protects mice from maximal electroshock-induced seizures. The aim of this study was to determine possible interactions between TP-315 and different molecular targets, i.e. GABAA receptors, voltage-gated sodium channels, and human neuronal α7 and α4β2 nicotinic acetylcholine receptors. The influence of TP-315 on the viability of human hepatic HepG2 cells was also established using PrestoBlue and ToxiLight assays. It was found that the anticonvulsant activity of TP-315 results (at least partially) from its influence on voltage-gated sodium channels (VGSCs). Moreover, the title compound slightly affected the viability of human hepatic cells.

1,2,4-Triazole-based anticonvulsant agents with additional ROS scavenging activity are effective in a model of pharmacoresistant epilepsy

“…Therefore, to confirm the antioxidant potency of TP-10, TP-315, and TP-427 in in-vivo conditions, flow cytometric measurements of the total ROS level and mitochondrial potential were performed. Human brain-derived cells (U-87 MG) were exposed to a fixed concentration (10 mg/ml) of the compounds for 24 h. As it has been shown before in studies on TP-315 and TP-427, such a concentration remains non-toxic for human cells (HEK-293, HepG2) and is sufficient to generate the maximal anticonvulsant effect in mice subjected to the MES test 11,12 . As can be seen from Figure 2, there were also no visible changes in the morphology and viability of U-87 MG cells treated and untreated with the investigated 1,2,4-triazole-3-thiones.…”

“…Importantly, 4-hexyl-5-substituted-1,2,4-triazole-3-thione derivatives (TP-315, TP-427), apart from their antioxidant activity, were also confirmed to be voltage-gated sodium channel blockers 11,12 . It is suggested by the researchers that compounds combining both antioxidant and sodium channel blocking activities are to be characterised by superior neuroprotective effect as compared to compounds possessing only one of these features 33 .…”

“…MES test) and favourable ADME-Tox properties (long-lasting effect, low toxicity, lack of genotoxic properties, etc.) [10][11][12][13][14][15][16] . These compounds exhibited fast onset of action and some of them were able to potentiate the anticonvulsant activity of valproate, which is the most commonly prescribed antiepileptic drug.…”

“…These compounds exhibited fast onset of action and some of them were able to potentiate the anticonvulsant activity of valproate, which is the most commonly prescribed antiepileptic drug. The use of patchclamp and radioligand binding techniques allow us to elucidate that voltage-gated sodium channels play crucial role in the anticonvulsant activity of the above-mentioned compounds [10][11][12] . From the 1,2,4-triazole-3-thione derivatives investigated thus far, those with the most favourable properties ( Figure 1) have been selected for further studies in order to examine their ROS scavenging activity and possible protective effect in animal model of pharmacoresistant epilepsy (6 Hz test).…”

Antinociceptive screening of various 1,2,4-triazole-3-thione derivatives in the hot-plate test in mice

“…Quite recently, a novel group of compounds (i.e., 1,2,4-triazole-3-thione derivatives) has gained attention as potential anticonvulsant drugs in preclinical studies [16][17][18][19][20][21][22][23]. Molecular studies have revealed that agents comprising the 1,2,4-triazole-3-thione structure exerted anticonvulsant effects by affecting GABA A receptors and blocking sodium channels in neurons [18,21,22]. On the other hand, drugs influencing GABA A receptors and blocking sodium channels possess the antinociceptive properties in both preclinical studies and clinical settings [24][25][26][27][28].…”